1. Field of the Invention
This invention relates to a new formulation of a topical anesthetic and, more particularly, to a fast acting transdermal, topical anesthetic formulation having improved stability.
2. Description of the Related Art
Surgical techniques such as cosmetic resurfacing involving surgical ablation with an Erbium:YAG laser, and other laser procedures involving vaporization, excision, incision, and coagulation of soft tissue in medical specialties including dermatology, plastic surgery, podiatry, neurosurgery, gynecology, otorhinolaryngology (ENT), arthroscopy (knee surgery), and invasive and endoscopic general surgery, can only be performed after the highly sensitive nerve endings in the skin are anesthetized. The preferred method of administration of anesthetic is transdermally.
Skin, however, is a formidable barrier to the absorption of analgesics. Because the skin must serve as a barrier to the ingress of pathogens and toxic materials, and the egress of physiologic fluids, the skin is highly impermeable. Impermeability allows the skin to preserve its own integrity while simultaneously maintaining the delicate dynamic electrolyte balance of the body. Therefore, the skin functions both as a containment mechanism and as a microbial, chemical, radiation and thermal barrier.
This impermeability may be attributed to the nature of one very thin layer created by normal development and physiological changes in the skin. After cells are formed in the basal layer, they begin to migrate toward the skin surface, until they are eventually sloughed off. As they undergo this migration, they become progressively more dehydrated and keratinized. When they reach the surface, just prior to being discarded, they form a thin layer of dense, metabolically inactive cells approximately ten microns (10-15 cells) thick, the stratum corneum or "cornified layer". As a result of the high degree of keratinization of the cells which comprise the stratum corneum, a formidable barrier is created. Absorption through a mucosal surface is generally efficient because the stratum corneum is absent. Therefore, any formulation to be utilized as an efficient topical, transdermal anesthetic must be capable of being readily absorbed through the skin.
In addition to the thickness and integrity of the stratum corneum epidermis, percutaneous or transdermal absorption can significantly alter drug kinetics and depends on a variety of factors including site of application, size of active drug molecule, permeability of the membrane of the transdermal drug delivery system, state of skin hydration, pH of the drug, drug metabolism by skin flora, lipid solubility, and alteration of blood flow in the skin by additives and body temperature.
Certainly, it is well known to use topical, transdermal anesthetics, in dental applications such as in applying an anesthetic to the gum prior to injecting anesthetic. In mucous membranes, such as the lining of the mouth, topical anesthetics are readily absorbed and work well. However, on skin, the mechanics and physiology of absorption are much different.
Transdermal anesthetics are also useful for numbing an area prior to venipuncture, such as blood drawing. Pain relief is especially important in the area of pediatrics, where even minimal pain may result in an anxious and uncooperative patient.
In addition to its advantages over intravenous delivery, other advantages of transdermal delivery include avoidance of risks associated with parenteral treatment, elimination of the inconveniences of parenteral treatment; and elimination of gastrointestinal irritation resulting from exposing the gastrointestinal tract to pharmaceutical actives, preservatives, tableting agents, and the like.
In the past, several types of topical anesthetic methodology have been tried, including freezing the skin. This is done most easily by applying ice or spraying the skin with a vapocoolant, a chemical which evaporates quickly. This then freezes the surface of the skin. An example of this is ethyl chloride (chloroethane). Unfortunately, ethyl chloride has many disadvantages. It is difficult to numb large areas with these methods and the effect is short-lived, rarely lasting more than a few seconds to a minute. Further, ethyl chloride is flammable and, when used to produce local freezing, adjacent skin areas must be protected by application of petrolatum. Finally, the thawing process may be painful, and freezing may lower local resistance to infection and delay healing.
Cocaine solutions are also known, and act by blocking the initiation or conduction of the nerve pulse. For example, TAC (a mixture of tetracaine, adrenaline and cocaine) essentially eliminates pain and increases hemostasis during suturing of an open laceration but is not effective on unbroken skin. Further, system levels of cocaine have been documented after simple application of TAC soaked-pledgets to an open wound, thus, emphasizing the need for calculating and the limiting the dose of cocaine administered. Strict limitation of the total dose of each component according to the patient's lean body weight is crucial. As with any narcotic, the potential exists for respiratory depression and oxygen desaturation with the moderately rapid absorption through any mucosa.
Lidocaine is highly effective and is the most commonly used local anesthetic in the United States, especially in the form of aqueous solutions of lidocaine hydrochloride (Xylocaine.RTM.), which are administered intravenously through either direct injection or continuous infusion. Lidocaine stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses thereby effecting local anesthetic action. Lidocaine is also formulated as a jelly (Xylocaine.RTM. 2%), ointment, and spray for use as an anesthetic. Unfortunately, these formulations are only effectively absorbed through mucosal surfaces, not the skin.
A more recently developed transdermal anesthetic that utilizes lidocaine is EMLA.RTM. cream (Eutectic Mixture of Local Anesthetics), which patients have found preferable to lidocaine infiltration or ethyl chloride spray. EMLA.RTM. is an oil-in-water emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 1:1 by weight (2.5% and 2.5%, respectively), and comprising 92% purified water. A eutectic mixture is a mixture that has a melting point lower than that of its ingredients; therefore these two anesthetics after being heated and mixed exist as a liquid oil at room temperature, rather than as crystals. EMLA.RTM. cream is described in U.S. Pat. Nos. 4,529,601 (Broberg, et al.) and 4,562,060 (Broberg, et al.), which teach the mixing of specific proportions of certain local anesthetic agents in the form of their base in order to form a homogenous oil having a melting point below 40.degree. C., preferably below 25.degree. C.
Like lidocaine, prilocaine is an amide-type local anesthetic agent. Amides, are favorable as anesthetic agents, as opposed to esters, which are more sensitizing and can produce redness, swelling, irritation, itching, and other reactions. Unfortunately, methemoglobinaemia and cyanosis appear to occur more frequently with prilocaine than with other local anesthetics. Methemoglobinaemia describes the formation of oxidized iron compound in the heme protein of the red blood cell. It is a disease state of the erythrocyte. Cellular oxidant stress causes a structural change in the hemogloblin. If the oxidant stress is too great, methemoglobin levels rise and erythrocyte function is compromised. Symptoms usually occur when doses of prilocaine hydrochloride exceed about 8 mg per kg body-weight but the very young may be more susceptible. For the average person of 70 kg, this represents a dose of 560 mg. This severely limits the size of the area to be anesthetized.
A major inconvenience with EMLA.RTM. is that local anesthesia of intact skin is not achieved until at least 60 minutes following application. For more invasive procedures, such as split skin graft harvesting, at least two hours may be required. This delay in onset is a significant disadvantage, as it is a great inconvenience for both patients and medical staff. Such delay is particularly a problem in the area of pediatrics, where any additional time spent awaiting treatment only contributes to the anxiety of the patient.
Another disadvantage with EMLA.RTM. cream is that, for deep penetrative effect, it is necessary that the cream be applied under an occlusive dressing. Specifically, a bilayer of laminate and absorbent cellulose is taped to the area of the skin to be anesthetized. Such a dressing is inconvenient and messy.
It would be desirable, therefore, to have a topical, transdermal anesthetic which derives the benefits of both lidocaine and prilocaine, but which is free of all the above-described problems associated therewith.
Accordingly, it is an object of the present invention to provide a topical, transdermal anesthetic utilizing prilocaine, without such pronounced dosage limitations characteristic of other prilocaine-containing anesthetics.
Another object of the present invention is to provide a topical, transdermal anesthetic which exhibits comparably rapid onset.
Yet another object of the present invention is to provide a topical, transdermal anesthetic which is not dependent upon occlusive dressing for rapid absorption through the skin.